NETO1 Regulates Postsynaptic Kainate Receptors in CA3 Interneurons During Circuit Maturation

Kainate type ionotropic glutamate receptors (KARs) are expressed in hippocampal interneurons and regulate interneuron excitability and GABAergic transmission. Neuropilin tolloid-like proteins (NETO1 and NETO2) act as KAR auxiliary subunits; however, their significance for various functions of KARs in GABAergic interneurons is not fully understood. Here we show that NETO1, but not NETO2, is necessary for dendritic delivery of KAR subunits and, consequently, for formation of KAR-containing synapses in cultured GABAergic neurons. Accordingly, electrophysiological analysis of neonatal CA3 stratum radiatum interneurons revealed impaired postsynaptic and metabotropic KAR signaling in Neto1 knockouts, while a subpopulation of ionotropic KARs in the somatodendritic compartment remained functional. Loss of NETO1/KAR signaling had no significant effect on development of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and N-methyl-D-aspartate (NMDA)-receptor-mediated glutamatergic transmission in CA3 interneurons, contrasting the synaptogenic role proposed for KARs in principal cells. Furthermore, loss of NETO1 had no effect on excitability and characteristic spontaneous network bursts in the immature CA3 circuitry. However, we find that NETO1 is critical for kainate-dependent modulation of network bursts and GABAergic transmission in the hippocampus already during the first week of life. Our results provide the first description of NETO1-dependent subcellular targeting of KAR subunits in GABAergic neurons and indicate that endogenous NETO1 is required for formation of KAR-containing synapses in interneurons. Since aberrant KAR-mediated excitability is implicated in certain forms of epilepsy, NETO1 represents a potential therapeutic target for treatment of both adult and early life seizures.